Coated endovascular stent

ABSTRACT

An implantable stent is coated with a material that attracts heparin and with which heparin forms a bond. The stent is exposed to a heparin containing solution just prior to implantation or is first implanted and then exposed to heparinized blood. As heparin becomes detached from the stent, the implantation site is exposed to heparin to restore an effective level and thereby prevent thrombosis.

CROSS REFERENCE

This is a divisional application of application Ser. No. 10/877,527filed on Jun. 24, 2004, which is a divisional application of applicationSer. No. 08/847,763 filed on Apr. 24, 1997, now U.S. Pat. No. 6,776,792.

BACKGROUND OF THE INVENTION

The present invention relates to endovascular stents and moreparticularly pertains to coatings that are applied to stents in order toreduce thrombogenicity.

Stents are implanted within blood vessels in an effort to maintain theirpatency by preventing collapse of the lumen and/or by impedingrestenosis. Unfortunately, the presence of a foreign object within theblood flow may have a thrombogenic effect. It has therefore been foundto be desirable to use various anti-coagulant drugs in an effort toreduce the likelihood of the development of restenosis and provide anantithrombogenic effect.

A drug that has been found to be particularly effective for such purposeis heparin. By maintaining an effective concentration of the drug in andabout the implantation site until the stent is encapsulated by tissue,the risk of thrombogenesis is substantially mitigated. To that end,various approaches have been employed in the administration of heparin.

While the systemic administration of heparin can cause the implantationsite to be subjected to an effective level of heparin, such level ofheparin would necessarily also be present throughout the rest of thebody which can lead to undesirable side effects such as bleeding. It hastherefore been recognized that a regimen wherein the heparin issubstantially constrained to the implantation site is far moredesirable. An approach that has been devised to achieve such endrequires the coating or impregnation of the stent itself with heparin.The heparin is thereby concentrated where it is most needed while itspresence, and consequently its effect, throughout the rest of the bodyis minimized.

Disadvantages associated with heretofore known heparinized stentsinclude, the limited shelf life of such devices, the fact the heparin isdegraded when the stent is sterilized either by heat or by exposure toethylene dioxide, the inability of the physician to alter the dosagethat the patient is subjected to and the inability to replenish anyheparin that may be lost while the device is deployed. Additionally, thecost of heretofore known heparinized stent devices has been very high asit necessarily includes the costs associated with the stringentregulatory requirements attendant a drug containing device.

The prior art has been unable to overcome these disadvantages andshortcomings and a new approach is needed to safely, effectively, andeconomically deliver heparin to an implantation site.

SUMMARY OF THE INVENTION

The present invention provides for the coating of an implantableendovascular device to facilitate the subsequent loading of heparin ontoits surface. Such loading can be achieved in vitro just prior toimplantation or preferably, in vivo after the device is in place. As aresult, the device has a considerably longer shelf-life thanheparin-containing devices, the need for special handling andsterilization procedures associated with heparin-containing devices isobviated, and the dosage of heparin can be readily tailored to anindividual patient's needs including any adjustment that may be requiredafter the device has been deployed. An additional advantage provided bysuch a device is that it is not subject to the stringent regulatoryrequirements associated with drug-containing devices.

More particularly, the present invention provides for the coating ofstent surfaces with a material or combination of materials that areselected for their ability to adhere to the stent surface, to attractheparin and to form preferably an ionic bond therewith. The heparin isattracted by and attaches to functional groups incorporated in thecoating which may include primary, secondary, and/or tertiary amines orother functionalities such as carboxyl groups.

The heparin-attracting coating may be applied so as to encapsulate theentire stent or alternatively, to cover only selected surfaces thereof.By limiting coverage to only the inner surface of the stent, i.e., thesurface that is directly exposed to blood flow, a much higher level ofheparin can be loaded onto the stent than would be safe if such levelwere in direct contact with the vessel wall. A toxic effect on thevessel wall is thereby avoided while the blood is exposed to a moreeffective concentration of heparin. Alternatively, it may be deemedsufficient to coat only the ends of the stent, i.e., where disturbanceof flow is greatest and where thromboses are most likely to occur.

The coating may be applied by different processes such as by dipping,spraying or molding. The preferred method is by plasma depositionwherein a base layer, selected for its ability to adhere to the stentsurface, is first deposited on the stent followed by the deposition of atop layer thereon that is selected for its ability to bond to the baselayer and to avail the appropriate functional groups for bonding to theheparin.

These and other features and advantages of the present invention willbecome apparent from the following detailed description which, taken inconjunction with the accompanying drawings, illustrates by way ofexample the principles of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of an implantable stent.

FIG. 2 is a greatly enlarged, schematic, cross-sectional view of aportion of the stent of the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

A wide variety of different stent configurations have been devised toaddress various issues inherent in their use and function. Additionally,various materials have been employed in their construction includingmetals and polymers. Both the degree of turbulence caused by aparticular stent configuration when subjected to blood flow as well asthe material from which it is constructed affects the degree ofthrombogenicity associated with a particular stent device. The presentinvention provides a coating for such stents to which heparin becomesattached and thus serves to reduce or eliminate thrombosis formation.Moreover, the stent's coating allows the heparin to be loaded thereonimmediately before the implantation procedure or after the stent is inplace.

Critical requirements for the coating of the present invention includethat it adheres to the stent surface and that it has functional groupsthat attract heparin and to which heparin bonds. Functional groups thatare known to have the requisite affinity for heparin include primary,secondary, and tertiary amines wherein primary amines are preferred dueto their enhanced affinity. Alternatively, carboxyl groups may be used.The functional groups must include positively charged entities thatserve to attract the negatively charged entities associated with theheparin. Such attraction facilitates the formation of an ionic bond.

The coating can be applied by different processes such as by dipping,spraying, molding or by plasma deposition. Plasma deposition ispreferred and first requires the deposition of a base layer or primerthat prepares the surface of the stent to receive the functionalitygroup containing substance. In the preferred embodiment, a metallicstent is first plasma deposited with methane gas leaving a film on thesurface of the stent wherein the methane molecules are oriented with thecarbon against the stent and the hydrogen exposed. A top layer thatincludes the desired functionalities is then deposited on the baselayer. Such second layer may be formed by the plasma deposition ofammonia gas to leave the primary amine functional groups extending fromthe stent surface. Other chemicals such as alkylamine, nitrile compoundsor amine containing monomers can also be used to plasma deposit aminefunctionalities on the surface. In the event a mixture of primary,secondary, and tertiary amines is deposited by such methods it ispreferred that the primary amine constitutes a greater percentage of themixture due to its greater affinity for heparin. Alternatively, thedeposition of carboxyl functional groups can be achieved by the plasmadeposition of monomers like methyl methacrylate or acrylic acid.

The resulting coating thickness should be 0.001 inch or less while athickness less than 1 micron is preferred. Although it may be desirableto have a uniform concentration of functional groups extending from thesurface, it is not critical to the function of the coating. On the otherhand, a concentration of at least 54 picamoles/stent must be achieved inorder to ensure that heparin becomes attached at an effective level.

The coating may be applied to the entire stent or just to selectedsurfaces thereon. FIG. 1 generally illustrates a stent 12 in itsdeployed state and serves to identify the vessel wall-facing surface 14,the blood flow-facing surface 16, its upstream edge 18, and itsdownstream edge 20. By coating only the surfaces facing the blood flow,a concentration of heparin can be loaded thereon that would be toxic tothe vessel wall tissue if it were to be present on the surfaces indirect contact with the vessel wall. Alternatively, it may be sufficientto exclusively coat the upstream and/or downstream edges of the stentfor a particular stent configuration implanted in a particular patientas thrombosis is most likely to occur at such interfaces due toturbulence induced by their presence in the blood flow.

After the coating process is completed, the coated stent is cleaned andsterilized and appropriately packaged for long-term storage. Due to theabsence of any degradable drugs or substances on the stent, a fairlyextended shelf-life can be expected.

The stent of the present invention can be used in two different ways. Afirst use calls for the stent to be implanted in the form in which ithad been stored, without having heparin loaded thereon. Once in place,it is contacted with heparinized blood, either by an injection ofheparin via a catheter extended to a position just upstream of theimplantation site or by IV. As the heparin macromolecules 22 pass by thefunctional groups 24 in the coating 26, the heparin is attracted theretoand becomes attached (FIG. 2). Heparin that does not attach, quicklybecomes diluted downstream of the implantation site to levels that donot adversely affect the patient. Subsequent heparin flow past theimplantation site can cause more and more heparin molecules to be pulledfrom the blood flow until the stent coating is saturated. Once attached,heparin can inhibit coagulation by binding with anti-thrombin III and/orother factors of the coagulation cascade. Should a heparin moleculebecome detached, it is replaced by other heparin molecules still presentin the blood flow. Alternatively, an additional dosage of heparin can beadministered.

Alternatively, the physician may pre-treat the stent prior toimplantation by flushing it with, for example, a heparinized salinesolution. In this way, the physician can easily and precisely adjust theheparin level by controlling the concentration of the heparin in thesaline solution and/or controlling the exposure time thereto. Onceimplanted, the heparin level can be increased or replenished byintroducing heparin into the blood flow upstream of the implantationsite as was described above. The heparin level is maintained on thestent until the natural healing processes cause the stent surfaces to becompletely covered by tissue at which point thrombogenicity ceases to beof concern.

While a particular form of the invention has been illustrated anddescribed, it will also be apparent to those skilled in the art thatvarious modifications can be made without departing from the spirit andscope of the invention. Accordingly, it is not intended that theinvention be limited except by the appended claims.

1. A method of making a medical device comprising: providing animplantable support structure; depositing a coating on the supportstructure, the coating including functional groups that attract heparin;implanting the support structure in the patient's vasculature; andexposing the implanted support structure to heparinized blood such thatheparin attaches to the coating.
 2. The method of claim 1, whereinheparin attaches to the coating via ionic bonds.
 3. The method of claim1, wherein exposing the implantable support structure to heparinizedblood comprises delivering heparin from a catheter to the patient. 4.The method of claim 1, wherein the coating is deposited on the entiresupport structure.
 5. The method of claim 1, wherein the supportstructure is configured such that upon implantation in a blood vessel,such support structure has surfaces that face the vessel walls andsurfaces that face the blood flow and wherein the coating is exclusivelydeposited on the surfaces that face the blood flow.
 6. The method ofclaim 1, wherein the support structure is configured such that uponimplantation in a blood vessel, such support structure has surfaces thatface the vessel walls, surfaces that face the blood flow and an upstreamedge and a downstream edge and wherein the coating is exclusivelydeposited on at least one of the edges.
 7. The method of claim 1,wherein the coating is deposited on the support structure by dipping,spraying or molding.
 8. The method of claim 1, wherein the coating isdeposited on the support structure by plasma deposition.
 9. The methodof claim 1, wherein the coating is deposited by first depositing a baselayer, selected for its ability to adhere to the support structure andthen depositing thereon a top layer selected for its ability to bond tothe base layer and avail the functional groups for attachment to theheparin.
 10. The method of claim 1, further comprising repeatedlyexposing the implanted support structure to heparinized blood in orderto maintain a heparin level on the stent.
 11. The method of claim 1,wherein the functional groups are selected from a group consisting ofamine and carboxyl groups.
 12. A method of making a medical device,comprising: providing an implantable support structure; depositing acoating on the support structure, the coating including functionalgroups that attract heparin, bond with heparin, or a combinationthereof, when the coating is exposed to heparin; sterilizing and storingthe support structure having the coating deposited thereon; exposing thecoated support structure to a heparin-containing solution; andimplanting the structure in the patient's vasculature.
 13. The method ofclaim 12, wherein the coating is deposited on the entire supportstructure.
 14. The method of claim 12, wherein the support structure isconfigured such that upon implantation in a blood vessel, such supportstructure has surfaces that face the vessel walls and surfaces that facethe blood flow and wherein the coating is exclusively deposited on thesurfaces that face the blood flow.
 15. The method of claim 12, whereinthe support structure is configured such that upon implantation in ablood vessel, such support structure has surfaces that face the vesselwalls, surfaces that face the blood flow and an upstream edge and adownstream edge and wherein the coating is exclusively deposited on atleast one of the edges.
 16. The method of claim 12, wherein the coatingis deposited on the support structure by dipping, spraying or molding.17. The method of claim 12, wherein the coating is deposited on thesupport structure by plasma deposition.
 18. The method of claim 12,wherein the coating is deposited by first depositing a base layer,selected for its ability to adhere to the support structure and thendepositing thereon a top layer selected for its ability to bond to thebase layer and avail the functional groups for attachment to theheparin.
 19. The method of claim 12, further comprising exposing theimplanted support structure to heparinized blood in order to maintain aheparin level on the support structure.
 20. The method of claim 12,wherein the functional groups are selected from a group consisting ofamine and carboxyl groups.
 21. The method of claim 12, wherein thebonding of the coating with heparin comprises a combination of ionicbonding and covalent bonding.
 22. The method of claim 12, wherein thesupport structure comprises a stent.